Staff Writer

Now that there's a new approved systemic lupus erythematosus (SLE) therapy for the first time in 56 years, patients and rheumatologists will only have to bide their time for about two more weeks before they can get Benlysta.

"The Benlysta commercialization team is in place and raring to go," said Barry A. Labinger, executive vice president and chief commercial officer of Human Genome Sciences Inc. (HGSI), during a conference call.

Reflecting a confidence in the potential FDA nod, which came after the markets closed Wednesday, Rockville, Md.-based HGSI and partner GlaxoSmithKline plc, of London, built Benlysta inventory in 2010 and have enough for at least a year. They also created a U.S. sales force of about 150, which is ready to talk to rheumatologists and support patients with reimbursement and access programs. HGSI President and CEO H. Thomas Watkins said he expects Benlysta to be available to physicians and patients before the end of March.

Benlysta (belimumab) is a recombinant, fully human, IgG1λ monoclonal antibody that is delivered via intravenous infusion for patients with active, autoantibody-positive SLE who are receiving standard therapy, including corticosteroids, antimalarials, immunosuppressives and nonsteroidal anti-inflammatory drugs.

Prior to the FDA's Wednesday evening approval, the last approved drugs to treat lupus were Plaquenil (hydroxychloroquine) and corticosteroids in 1955, with aspirin approved 1948, according to the FDA.

Benlysta is the only medicine specifically developed to treat SLE, which can cause arthritis-like symptoms, cardiovascular problems, anemia and other blood disorders, malar rash and irreversible organ damage, often leading to death.

Sandra C. Raymond, president and CEO of the Lupus Foundation of America called the FDA approval "a significant first step toward reaching our goal of developing an arsenal of new, safe, effective and tolerable treatments."

Shares of HGSI (NASDAQ:HGSI) closed up 13 percent Thursday to close at $29.03 in trading that was about 15 times the daily average. GlaxoSmithKline (NYSE:GSK) lost 18 cents, closing at $38.40.

Benlysta has blockbuster potential for HGSI and GSK, who are working together under a 2006 co-development and commercialization agreement. Annual global sales forecasts from analysts range from $2 billion to $5 billion..

"The key question remains what the launch will look like," said Piper Jaffray & Co. analyst M. Ian Somaiya. "We believe the broad label and reasonable pricing could engender widespread physician and patient enthusiasm, but ultimately, uptake will be dependent on appropriate formulary status and establishment of a permanent [Medicare] J code for Benlysta, which could take six months."

During its most recent quarterly financial results report on Feb. 24, HGSI CFO David Southwell said the company had more than $933 million in cash and investments and the "financial strength required to support a world-class launch of Benlysta while continuing to advance and broaden our research and development pipeline."

A decision from the European Medicines Agency on the Benlysta marketing authorization application submitted in June 2010 is anticipated in the second half of 2011. GSK has submitted regulatory applications in Canada, Australia, Switzerland, Russia, Brazil and the Philippines.

HGSI said it invested in commercial infrastructure, expertise and product manufacture in 2010 required to launch and support Benlysta. The company also said it was building its own commercialization team based in Switzerland and with local organizations in Germany, France and Spain to work with GSK in Europe. Outside the U.S., GSK will lead local implementation, with HGSI and GSK sharing costs and profits equally.

HGSI said it continued to manufacture and build Benlysta inventory in 2010 and has inventory available to meet global needs for at least one year, adding that its large-scale manufacturing facility has sufficient capacity to provide worldwide supply for the first two to three years following launch. In July 2010, HGSI announced an agreement with Lonza that is expected to triple Benlysta capacity in 2012.

Labinger said there are an estimated 325,000 patients in the U.S. diagnosed with SLE who are treated by rheumatologists. About two-thirds of them suffer moderate to severe forms of the disease at some point, and those 200,000 represent Benlysta's U.S. target market, he said.

Although there will be an annual cost of about $35,000 for the average patient, Labinger said that HGSI and GSK will have programs to assist patients in need with access to free supplies or for help with co-pays.

J.P. Morgan analyst Cory Kasimov said that while the FDA outcome was widely expected, "we nevertheless view it as a transformative event. HGSI now has an approved biologic with multi-billion-dollar peak sales potential that could possibly enjoy a prolonged period of monopoly-like status."

Jefferies & Co. analyst Jeffrey Holford wrote that despite some restrictions, "Given the need for new treatments in this area, we still expect Benlysta to be able to generate peak sales of around $2 billion, split between the two companies."

HGSI said that the label for Benlysta will state that "The efficacy of belimumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus, and has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of belimumab is therefore not recommended in these situations."

Labinger said the labeling "gives us everything we need to help ensure that Benlysta realizes its full therapeutic and commercial potential."

Curtis Rosebraugh, director of the FDA's Office of Drug Evaluation, said in a statement that "Benlysta, when used with existing therapies, may be an important new treatment approach for health care professionals and patients looking to help manage symptoms associated with this disease."

However the FDA noted in its approval remarks that two clinical studies involving 1,684 patients excluded patients who had received prior B-cell targeted therapy or intravenous cyclophosphamide, and those who had active lupus involving the kidneys or central nervous system. The agency also said that results "suggested, but did not definitively establish, that some patients had a reduced likelihood of severe flares, and some reduced their steroid doses."

Moreover, the FDA said that African American patients and patients of African heritage participating in the two studies "did not appear to respond to treatment with Benlysta."

HGSI and GSK will provide patients with a medication guide to inform them of risks and have agreed to conduct an additional study of African American patients and patients of African heritage to further evaluate safety and effectiveness.

Leerink Swann analyst Joseph P. Schwartz noted that the label and safety concerns do not appear to be major issues, calling the indication "sufficiently broad," the safety language "not a constraint" and the medication guide requirement "very benign."

J.P. Morgan's Kasimov viewed the label as "favorable" and not "overly restrictive, despite mentions of the FDA's well known concerns (use in African Americans and patients with severe CNS/renal involvement)."

Monness, Crespi, Hardt & Co. analyst Avik Roy wrote that the FDA label "is fair and balanced. The wording of the Benlysta package insert is conservative."

In November an FDA panel in a 13-to-2 vote recommended approval for Benlysta as a treatment for adults with SLE, which primarily affects women of childbearing age, although men, children and teenagers have been known to develop the condition. (See BioWorld Today, Nov. 17, 2010.)

The majority of the committee said that HGSI's two Phase III trials of Benlysta 10 mg/kg – which met their primary endpoints – demonstrated substantial evidence of efficacy for reducing disease activity in patients with active, auto-antibody-positive SLE.

However several panelists insisted that the FDA ensure Benlysta's labeling emphasize that the drug was not studied in patients with more severe forms of lupus, such as renal impairment and central nervous system lupus. Some panelists also raised concerns about the lack of Benlysta's efficacy in African American patients in HGSI's Phase III studies, which is a concern because patients of African American or African heritage are known to have more aggressive SLE and develop renal disease more frequently, often leading to worse outcomes.

FDA drug reviewers had questioned whether the modest benefit of Benlysta in treating some lupus patients is worth the potential increased risk of death, infection or adverse neuropsychiatric effects, including suicide.

Regulators also noted that patients with serious SLE manifestations, such as renal and central nervous system lupus, in whom immunosuppressives and other biologics likely will be needed, were excluded from HGSI's Phase III studies, leaving it unclear about the safety of combining Benlysta with other lupus treatments in populations with more serious disease. Those questions, drug reviewers said in briefing documents released ahead of the FDA's Arthritis Advisory Committee decision, created "dilemmas" for HGSI's biologic license application for Benlysta, which was submitted in June. (See BioWorld Today, June 11 , 2010, and Nov. 15, 2010.)

For decades, lupus has devoured drug developers like the wolf for which it is named. Genelabs Technologies Inc. sought to use its hormone drug Prestara (prasterone) to increase bone mineral density in lupus patients, but that didn't pan out in Phase III trials.

La Jolla Pharmaceutical Co.'s attempt to delay renal flares with B-cell targeted Riquent (abetimus sodium) also failed in Phase III. Ditto for Aspreva Pharmaceuticals Corp.'s immunosuppressive drug CellCept (oral mycophenolate mofetil), which was aimed at decreasing proteinuria and stabilizing serum creatinine levels. And Roche AG's B-cell targeted Rituxan (rituximab) failed to normalize kidney function or generate a clinical response on the BILAG (British Isles Lupus Assessment Group) scale, which measures lupus disease activity by organ system. There were other lupus failures as well: Roche AG's ocrelizumab, Bristol-Myers Squibb Co.'s abatacept, Teva Pharmaceutical Industries Ltd.'s edratide, and even a Phase II trial of HGSI's own Benlysta. (See BioWorld Insight, Nov. 22, 2010.)

HGSI began to crack the lupus clinical trial design code in Phase II. The company came up with a composite primary endpoint it called the SLE responder index.

The index is composed of three measurements: the SELENA SLEDAI scale to assess improvement in disease activity; the BILAG Classic Index to detect clinically relevant worsening of an organ system; and the PGA scale to detect worsening in a patient's general health.

Although HGSI's Phase II Benlysta trial failed, the company was able to identify a subset of serologically active patients who experienced statistically significant improvement, and it focused on that subgroup for Phase III.

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